Synlett 2003(9): 1339-1343
DOI: 10.1055/s-2003-40332
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Preparation of Sialyl Donors Carrying Functionalized Ester Substituents: Effects on the Selectivity of Glycosylation

Akihiro Ishiwata, Yukishige Ito*
RIKEN (The Institute of Physical and Chemical Research), 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan
Fax: +81(48)4624680; e-Mail: yukito@postman.riken.go.jp;
Further Information

Publication History

Received 28 April 2003
Publication Date:
30 June 2003 (online)

Abstract

Methylthio sialyl donors having various ester substituents were prepared systematically. Nucleophilic displacement of methyl ester with Ph3SiSH and Cs2CO3 followed by in situ alkylation with RX or esterification with R-OH/DCC afforded these compounds in good yields. Glycosylations promoted by NIS-TfOH were examined in order to examine the effect of substituent of the ester portion. When conducted in CH3CN, enhanced α-selectivities were observed for cyanomethyl, 2-cyanoethyl, 2-cyanobenzyl, and 2-nitrobenzyl esters, implying that these substituents are effective enhancing the solvent effect of acetonitrile, possibly by stabilizing the β-oriented nitrilium ion.

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Typical procedure (compound 1h): To the solution of compound 1a (209 mg, 0.401 mmol), 2,6-di-t-butyl-4-cresol (18 mg, 0.08 mmol) and Ph3SiSH (352 mg, 1.20 mmol) in dry DMF (5 mL) was added Cs2CO3 (352 mg, 1.08 mmol) and the mixture was stirred at 80 °C for 8 h. After cooling down to ice-water temperature, 2-nitrobenzyl bromide (261 mg, 1.21 mmol) was added and stirring continued for 4 h at 0 °C. The reaction was saturated aq KHSO4 and extracted with EtOAc. The organic layer was washed with brine, dried (Na2SO4), and concentrated in vacuo. The residue was purified by flash chromatography (hexane-EtOAc, 10:1-1:2) to give compound 1h (212 mg, 82%).

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Stabilization of anomeric cation by multiple molecules of acetonitrile was proposed. See refs. [3c] [d]

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NMR (CD3OD, 400 MHz) δ 1.72 (1 H, t, J = 12.0 Hz, H-3Neu5Ac), 1.85, 1,86, 1.97, 1.98, 1.99, and 2.10 (each 3 H, s, 6Ac), 2.71 (1 H, dd, J = 12.0 Hz, 4.0 Hz, H-3Neu5Ac), 3.37-3.42 (1 H, m, H-6Gal), 3.52-3.60 (3 H, m, H-5Gal, H-6Glc, H-2Gal), 3.83-3.88 (3 H, m, H-6Glc, H-6′Glc, H-5Gal), 3.97-4.09 (3 H, m, H-4Glc, CH 2=CHCH2, H-5Neu5Ac), 4.09 (1 H, dd, J = 11.2 Hz, 8.4 Hz, H-2Gal), 4.14 (1 H, dd, J = 12.4 Hz, 5.2 Hz, H-9Neu5Ac), 4.14 (1 H, dd, J = 12.4 Hz, 5.2 Hz, H-9Neu5Ac), 4.17-4.25 (2 H, m, H-9Neu5Ac, CH 2CH=CH2), 4.28 (1 H, dd, J = 11.2 Hz, 8.4 Hz), 4.39 (1 H, d, J = 12.0 Hz, Bn), 4.41 (1 H, dd, J = 12.4 Hz, 3.2 Hz, H-9Neu5Ac), 4.49 (1 H, d, J = 12.4 Hz, Bn), 4.54 (1 H, d, J = 12.0 Hz, Bn), 4.59 (1 H, d, J = 12.0 Hz, Bn), 4.69 (1 H, dd, J = 9.6 Hz, 2.4 Hz, H-3Gal), 4.76 (1 H, d, J = 12. 0 Hz, Bn), 4.81 (1 H, d, J = 7.2 Hz, H-1Gal), 4.88-4.96 (2 H, m, Bn), 4.98-5.03 (1 H, m, CH2CH=CH 2), 5.03-5.23 (2 H, m, CH2CH=CH 2, H-4Neu5Ac), 5.16 (1 H, d, J = 8.4 Hz, H-1Gal), 5.18 (1 H, d, J = 12.4 Hz, Bn), 5.38 (1 H, d, J = 2.4 Hz, H-4Gal), 5.39 (1 H, dd, J = 8.0, 2.4 Hz, H-7Neu5Ac), 5.66-5.77 (2 H, m, H-8Neu5Ac, CH2CH=CH2), 6.82-7.90 (24 H, m, Ar).